Chronic Skin-Specific Inflammation Promotes Vascular Inflammation and Thrombosis

Abstract

Patients with psoriasis have systemic and vascular inflammation and are at increased risk for myocardial infarction, stroke, and cardiovascular death. However, the underlying mechanism(s) mediating the link between psoriasis and vascular disease is incompletely defined. This study sought to determine whether chronic skin-specific inflammation has the capacity to promote vascular inflammation and thrombosis. Using the KC-Tie2 doxycycline-repressible (Dox-off) murine model of psoriasiform skin disease, spontaneous aortic root inflammation was observed in 33% of KC-Tie2 compared to 0% of control mice by 12 months of age (P=0.04) and was characterized by the accumulation of macrophages, T-lymphocytes and B-lymphocytes and reduced collagen content and increased elastin breaks. Importantly, aortic inflammation was preceded by increases in serum TNF-α, IL-17A, VEGF, IL-12, MCP-1 and S100A8/A9 as well as splenic and circulating CD11b+Ly-6Chi pro-inflammatory monocytes. Doxycycline treatment of old mice with severe skin disease eliminated skin inflammation and aortic root lesion presence in 1 year old KC-Tie2 animals. Given the bi-directional link between inflammation and thrombosis, arterial thrombosis was assessed in KC-Tie2 and control mice; mean time to occlusive thrombus formation was shortened by 64% (P=0.002) in KC-Tie2 animals; doxycycline treatment returned thrombosis clotting times to control mouse levels (P=0.69). These findings demonstrate that sustained skin-specific inflammation promotes aortic root inflammation and thrombosis and suggest that aggressive treatment of skin inflammation may attenuate pro-inflammatory and prothrombotic pathways that produce cardiovascular disease in psoriasis patients.

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

“…This phenotype is strikingly similar to common manifestations of human psoriasis, with marked acantosis, hyperkeratosis, and a nucleated cell infiltrate. Furthermore these mice also display severe aortic inflammation, a serious cardiovascular complication observed in some chronic psoriasis suffers (39). These observations highlight the importance of examining IL-1R1-mediated inflammation in psoriasis and further highlight the potential importance of TIR8/SIGIRR as a critical signaling mediator in this context.…”

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

“…Furthermore, rare use of topical antibiotic therapy on very severe K14-Rac1V12 -/+ mice may have impacted vascular disease progression. We also did not study patterns of thrombosis in this mouse model, which certainly should be done in the future (7,8). Furthermore, our use of a less-utilized atherosclerosis mouse model (Srb1…”

“…We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis. inflammation in the vasculature (7) and increase thrombosis (8). Recently, Winge et al (9) developed a potentially novel psoriasis mouse model, overexpressing a constitutively active mutant (Rac1 G12V ) of the GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), in keratinocytes specifically (K14-Rac1V12), resulting in a comparable pathophysiology between human and murine psoriasis spontaneously manifesting as early as 7 days after birth.…”

An Unusual Case of Pulmonary Embolism in a Patient with Psoriasis: Highlighting the Association between Psoriasis and Pulmonary Embolism

“…Others have suggested a more direct hypothesis that psoriasis-initiated skin and systemic inflammation cause insulin resistance, which promotes endothelial cell dysfunction, subsequent atherosclerosis and ultimately thromboembolic events 7 . It had been demonstrated that sustained skin-specific inflammation promotes inflammation and thrombosis and suggest that aggressive treatment of skin inflammation may attenuate pro-inflammatory and pro-thrombotic pathways that produce thromboembolic events in psoriasis patients 3 .…”

“…Clinical data have convincingly demonstrated that psoriasis patients have an increased risk for developing cardiovascular disease and an increased risk of thromboembolic events 2,3 . We report a unique case of a patient who suffered from both psoriasis and subsequent pulmonary embolism (PE).…”